Approximately one in eight of the persons in the United States registered as blind is handicapped as a direct result of glaucoma. This particular eye affliction may be defined as a rise in intra-ocular pressure which eventually damages the ocular function, with characteristic detrimental changes in the optic nerve and in the visual field, and deterioration of the visual field and sight resulting due to destruction of the optic nerve fibers.
In the normal or healthy eye, the average intra-ocular pressure is about 15.5 mm Hg with an upper limit of about 20.5 mm Hg. A measured intra-ocular pressure on the order of about 22-24 mm Hg is highly suggestive of glaucoma and serves to dictate the desirability of further investigations. Pressures in excess of about 30 mm Hg are most assuredly pathological in nature.
Damage to the eye can begin at intra-ocular pressures of greater than about 21 mm Hg. Additionally, damage to vision can also occur if pressures are below 20 mm Hg with progressive cupping and atrophy of the optic nerve and loss of the visual field, as characteristic in open angle glaucoma. In addition to pressures in excess of 30 mm Hg., pressure differentials of greater than about 5 mm Hg. in the eyes of an individual are nearly always suspect of pathological origin.
Glaucoma can be considered as primary and secondary, primary glaucoma being either congenital or capable of developing later in life. The adult onset form of glaucoma can be caused by angle closure, angle obstruction, or resistance to outflow, known as chronic simple glaucoma. Acute angle closure glaucoma results in red, painful eyes, an overt indication that some ocular abnormality exists. In the glaucomic condition termed as chronic simple glaucoma, however, the eyes appear as normal, and such condition can go undiagnosed for a long period of time. This condition can affect newborns, children, the middle-aged and elderly, with a tendency to affect both eyes and produce visual impairment in the latter stages rather than at onset.
The cause of chronic simple glaucoma is as yet largely unknown. In the normal eye, part of the epithelial lining of the inside of the eye, known as the ciliary body or the ciliary epithelium, secretes a fluid known as aqueous humor which circulates within the eye, supplying nutrients and removing waste products. This aqueous humor drains away through a filtering system called the trabecular meshwork into the canal of Schlemm and then into the aqueous veins, with the rate of aqueous production normally about 2 mm.sup.3 per minute. It is unlikely that a simple increase in the rate of aqueous humor output would result in glaucoma without some outflow resistance, and a permanent rise in the intra-ocular pressure is always the result of decreased outflow.
In addition to supplying nutrients and removing waste products, the aqueous humor also provides a constant pressure within the eye, with the normal pressure being from about 15 to about 20.5 mm Hg. In glaucoma this intraocular pressure may rise to as high as 30 mm Hg. and, in some exceptional cases, to about 70 mm Hg., with the damage produced by the increased pressure related to the degree of increase above normal. While some eyes appear to be more resistant to elevated pressures than others, prolonged elevated pressures will produce mechanical and vascular changes and pathology in the eye.
In glaucoma, the actual locus of damage is the optic nerve head, resulting in damage to the retinal nerve fibers passing out of the eye, the nerve fibers responsible for conducting visual impulses from the retina to the brain and damage to which results in visual loss or impairment. The responsibility for the perception of the field of vision resides with retinal receptor and damage thereto necessarily reduces the ability of the affected individual to see part or all of the visual field.
A constant relationship exists between retinal cells and nerve fibers, and as the nerve fiber damage appears in a selective and repeating fashion, the visual field effects may be said to be typical, although not exclusively so, of glaucoma.
The reasons why intra-ocular pressure rises above normal levels are not completely understood, as has been previously stated. In the instance of chronic simple glaucoma, the trabecular meshwork becomes resistant to the outflow of aqueous humor. This condition is known as open angle glaucoma. If the anterior chamber (the angle) becomes blocked by iris tissue the result is a sudden blockage of outflow of the aqueous humor and a concomitant, sudden rise in the pressure levels (closed angle glaucoma). Blockage of the anterior chamber angle can be brought about by any stimulus which enlarges the pupil of the eye, as for example darkness, reading or extended viewing, anxiety, reactions to medications such as adrenalin, and the like.
When the iris is withdrawn from the angle, but synechiae remain in the angle, the aqueous humor is unable to drain away and the intra-ocular pressure remains elevated (chronic congestive glaucoma).
In closed angle glaucoma, provided that the pressure is relatively easy to control, surgical procedures are prescribed, that of peripheral iridectomy wherein a small opening is cut in the iris using standard surgical or laser techniques. This procedure allows the aqueous humor trapped behind the iris to pass into the anterior chamber, which deepens, allowing unobstructed drainage through the angle. Angle closure glaucoma remains primarily a problem best dealt with by the employment of surgical procedures, although medical therapy is required in the initial stages and further may be required following surgery.
Surgery for open angle glaucoma, however, involves by-passing the trabecular meshwork and is dictated for those whose intra-ocular pressure cannot be adequately controlled by medication and for those who cannot or will not use their medication. In this surgical procedure, a small portion of the trabeculum is removed from under the scleral flap.
In spite of the success generally with the operation, management of open angle glaucoma by chemical means remains the first choice of action. The aim in medical as opposed to surgical therapy in glaucoma is to establish and maintain throughout each succeeding twenty-four hour period an intraocular pressure sufficiently low to prevent damage occurring within the eye and, in particular, to the optic disc. Since the cause of open angle glaucoma is not known, it is not presently possible to cure the underlying disease, but only to continuously control it.
According to statistics amassed by the National Institute of Health, more than one million individuals in the U.S. alone are afflicted with glaucoma, with females outnumbering males. Every year, on the order of two million visits are made to clinics in the U.S. for the diagnosis and treatment of glaucoma. Although surgical procedures are indicated in many cases, the majority of persons afflicted with glaucoma are subjected to medical, rather than surgical, treatment.
The chemicals which have been used to control glaucoma may be conveniently placed into three categories, dependent upon the primary mode of action: (a) those chemicals which increase the outflow of aqueous humor without affecting the aqueous humor production, (b) those chemicals which decrease the rate of aqueous humor production without affecting the outflow, and (c) those chemicals which affect both production and outflow of the aqueous humor.
The first group (a) encompasses the miotic drugs and the outflow resistance reducers, with the miotics divided into parasympathomimetics and anticholinesterase agents. Parasympathomimetics, the most widely used of which is pilocarpine, stimulate the action of acetylcholine which is responsible for, inter alia, the contraction of the pupil. If parasympathomimetics are administered alone, they are rapidly destroyed by the enzyme cholinesterase present in the blood, the ciliary bodies and the iris.
Anticholinesterase agents block cholinesterase and thereby increase the effect of acetylcholine in the eye. Also, this medication is unstable, readily oxidizing to an inactive form, and has many undesirable side effects including conjunctival irritation and allergic reactions. The most potent anticholine agent known is phospholine iodide, a synthetic acetylcholine analogue which binds very strongly to cholinesterase, and which may be used in relatively small amounts. However, the use thereof produces many systemic and ocular side effects, including an increase in the incidence of cataract formation.
There are many disadvantages in the use of miotic drugs in the treatment of glaucoma. Some of the drugs have relatively short durations of activity and therefore require frequent installation, a particular problem among elderly patients, among whom the disease is most common. Further, many patients report a darkening of vision due to pupil contraction and a significant diminution of color values. Additional disadvantages include topical allergic manifestations and the formation of iris cysts, as well as transitory discomfort such as nausea, vomiting, diarrhea, excessive salivation, sweating and dizziness.
Recently, a measure of interest has been expressed in the use of Cytochalasin B and ethylene-diaminetetraacetic acid (EDTA) to reduce the aqueous humor outflow resistance.
In the trabecular meshwork and the canal of Schlemm are located cytoplasmic actin microfilaments. Cytochalasin B is known to cause disruption of these filaments. It has been demonstrated that, following injection into the anterior chamber of the eye, Cytochalasin B causes a marked increase in aqueous humor outflow. However, this compound is also very cytotoxic. It is further known that the presence of calcium ions is necessary for cell adhesion and that the removal of calcium ions from the anterior chamber by the administration of EDTA exhibits an effect similar to that of Cytochalasin B. In common with most calcium antagonists, and unfortunately, EDTA is also very toxic.
A second group of drugs, the adrenergic agonists, affect both aqueous humor formation and outflow. The sympathetic effector cells in the eye have both alpha and beta type receptor sites. Stimulation of either of these sites reduces intra-ocular pressure, alpha site stimulation increasing outflow through the trabecular meshwork and beta site stimulation decreasing aqueous humor production at the ciliary body. However, the sympathetic pharmacology of the eye and, conversely, alpha and beta adrenoreceptor blocking agents also produce a lowering of the intra-ocular pressure. Even though adrenergic drugs have been employed in the management of glaucoma for over 60 years, these drugs also exhibit side effects which can be quite marked, the major effects being systemic in nature. Adrenalin and isoprotenerol, both used as adrenergic agents, can produce such side effects as conjunctival hyperaemia and pupil dilation, among others. Adrenalin is further unsuited for use by patients afflicted with cardiovascular diseases or hypertension, particularly significant as glaucoma tends to be a disease of the middle-aged and elderly.
Guanethidine is a post-ganglionic adrenergic neuron blocker which acts by impairing the release of noradrenaline from adrenergic nerve junctions. Used alone, this drug has little effect in lowering intraocular pressure and is often used in conjunction with adrenaline, administered prior to adrenaline medication.
Timolol.RTM., employed as a beta adrenergic blocker, lacks most of the undesirable side effects of pilocarpine, such as miosis, local irritation, headache and ciliary spasm, and also produces less conjunctival hyperemia than adrenalin. However, clinical results which have been obtained on the use of Timolol.RTM. have revealed that, used in eye drops, Timolol.RTM. can cause cardiovascular disturbances including bradycardia and systemic hypotension, some decrease in tear production and occasional bronchiospasms.
The third group of glaucoma treatment drugs are the systemic inhibitors of carbonic anhydrase, reducing intra-ocular pressure by acting to reduce the formulation of aqueous humor, the most commonly used of which is the 1,3,4-thiadiazole, acetazolamide (Diamox.RTM.). The inhibition of carbonic anhydrase acts to decrease the rate of production of aqueous humor without suppressing the production thereof completely. However, acetazolamide therapy is also associated with metabolic acidosis and, in many patients with renal impairment, this may cause confusion, weakness and pronounced hyperventilation. Further, long term acetazolamide therapy can result in formation of kidney stones, hepatic coma in patients with pre-existent liver diseases and, although rarely so, bone marrow depression. A proposed alternative to the use of acetazolamide has beer dichlorphenamide (Daranide). However, the undesirable side effects resulting during the use of this particular therapeutic compound, if anything, are more pronounced than those resulting from the use of acetazolamide.